Konieczna Iwona, Horvath Elizabeth, Wang Hao, Lindsey Stephan, Saberwal Gurveen, Bei Ling, Huang Weiqi, Platanias Leonidas, Eklund Elizabeth A
Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
J Clin Invest. 2008 Mar;118(3):853-67. doi: 10.1172/JCI33742.
Myeloproliferative disorders (MPDs) are characterized by cytokine hypersensitivity and apoptosis resistance. Development of a block in myeloid differentiation is associated with progression of MPD to acute myeloid leukemia (AML) and portends poor prognosis. Identifying molecular markers of this transition may suggest targets for therapeutic intervention. Interferon consensus sequence binding protein (ICSBP, also known as IRF8) is an interferon-regulatory transcription factor that functions as a leukemia tumor suppressor. In mice, ICSBP deficiency induces an MPD that progresses to AML over time, suggesting that ICSBP deficiency is sufficient for myeloproliferation, but additional genetic lesions are necessary for AML. Since activity of ICSBP is influenced by tyrosine phosphorylation state, we hypothesized that mutations in molecular pathways that regulate this process might synergize with ICSBP deficiency for progression to AML. Consistent with this, we found that constitutive activation of SHP2 protein tyrosine phosphatase synergized with ICSBP haploinsufficiency to facilitate cytokine-induced myeloproliferation, apoptosis resistance, and rapid progression to AML in a murine bone marrow transplantation model. Constitutive SHP2 activation cooperated with ICSBP deficiency to increase the number of progenitors in the bone marrow and myeloid blasts in circulation, indicating a block in differentiation. Since SHP2 activation and ICSBP deficiency may coexist in human myeloid malignancies, our studies have identified a molecular mechanism potentially involved in disease progression in such diseases.
骨髓增殖性疾病（MPD）的特征是细胞因子超敏反应和凋亡抗性。骨髓分化阻滞的发展与MPD进展为急性髓系白血病（AML）相关，并预示预后不良。确定这种转变的分子标志物可能提示治疗干预的靶点。干扰素共有序列结合蛋白（ICSBP，也称为IRF8）是一种干扰素调节转录因子，起白血病肿瘤抑制因子的作用。在小鼠中，ICSBP缺乏会诱导一种MPD，随着时间的推移会进展为AML，这表明ICSBP缺乏足以导致骨髓增殖，但AML的发生还需要其他基因损伤。由于ICSBP的活性受酪氨酸磷酸化状态的影响，我们推测调节这一过程的分子途径中的突变可能与ICSBP缺乏协同作用，促进进展为AML。与此一致的是，我们发现在小鼠骨髓移植模型中，SHP2蛋白酪氨酸磷酸酶的组成性激活与ICSBP单倍体不足协同作用，促进细胞因子诱导的骨髓增殖、凋亡抗性和快速进展为AML。组成性SHP2激活与ICSBP缺乏协同作用，增加骨髓中祖细胞和循环中髓系母细胞的数量，表明存在分化阻滞。由于SHP2激活和ICSBP缺乏可能共存于人类髓系恶性肿瘤中，我们的研究确定了一种可能参与此类疾病疾病进展的分子机制。
